System for dispensing pharmaceutically active compounds

ABSTRACT

A system for dispensing a clinically effective dose of an inhalable, pharmaceutically active compound, which system includes a dry powder inhaler device containing a powder containing the pharmaceutically active compound, wherein 
     (a) of the powder particles dispensed by the inhaler device (the &#34;metered DPI dose&#34;), at least 40% are less than about 10 microns in diameter at the point the particles exit the inhaler, 
     (b) the metered DPI dose is sufficient to produce a clinically effective result in a patient; and 
     (c) the amount of the compound in the metered DPI dose is not more than 70% of the minimal amount of the compound which, when dispensed in a pressurized metered dose inhaler, produces an equivalent clinically effective result in the same patient.

This is a continuation of application Ser. No. 08/654,006 filed May 29,1996, now U.S. Pat. No. 5,642,728, which is a continuation of U.S. Ser.No. 08/165,402, filed Dec. 10, 1993 abandoned.

This invention relates to a dry powder inhaler system for dispensing aclinically effective dose of a pharmaceutically active compound.

BACKGROUND OF THE INVENTION

Inhalable drugs are commonly used in the treatment of diseases of theairways, such as rhinitis, asthma, and chronic bronchitis. Examples ofsuch drugs include β2-adrenoreceptor agonists such as salbutamol,terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol,isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol,clenbuterol, procaterol, broxaterol, picumeterol, TA-2005, mabuterol andthe like, and their pharmacologically acceptable esters and salts;anticholinergic bronchodilators such as ipratropium bromide and thelike; glucocorsticosteroids such as betamethasone, fluticasone,budesonide, tipredane, dexamethasone, betamethasone, flucinolone,triamcinolone, mometasone, D-5519 and the like, and theirpharmacologically acceptable esters and salts; anti-allergy drugs suchas sodium cromoglycate and nedocromil sodium; expectorants; antibiotics;mucolytics; antihistamines; cyclooxygenase inhibitors; leukotrienesynthesis inhibitors; leukotriene antagonists, PLA2 inhibitors, PAFantagonists and prophylactics of asthma. In addition to these, somesystemically active drugs might be deliverable via inhalation.

Inhalable drugs are commonly administered using either a metered doseinhaler (MDI) or a dry powder inhaler (DPI). The MDI, in which the drugis dissolved or suspended in a liquid propellant mixture (sometimesincluding small amounts of a volatile organic or inorganic solvent)stored in a pressurized container, is currently the more widely useddevice. In using an MDI, a patient activates the device to release adose of the drug/propellant in coordination with inhalation through themouth.

In a DPI, the drug is in the form of a dry powder, sans propellant. Thistype of device dispenses drug by means of the particle cloud generatedby the airflow obtained upon patient inhalation through the mouth.

The aim of both the MDI and the DPI is to deposit a clinically effectiveamount of active compound in the lungs of the patient. By "clinicallyeffective amount of active compound" is meant that amount of activecompound which is required in order to effect the desired clinicalresponse.

If handled correctly, MDI's and many DPI's deliver pharmaceuticals tothe active site with approximately the same efficiency; however theamount of active substance which actually reaches the lungs in each casemay be only approximately 10% of the amount in the metered dose.Therefore, in order to ensure that a clinically effective amount ofactive compound reaches the lungs, this metered dose must necessarilycontain an amount of active compound many times greater than theclinically effective amount. The active compound which does not reachthe lungs is lost mainly in the apparatus itself, and in thegastrointestinal tract. This is disadvantageous, since loss of activesubstance in the apparatus is costly and may reduce efficiency further,by for example clogging the mouthpiece or inhalation channel. Moresignificantly for the patient, loss in the gastrointestinal tract cantrigger or accentuate side effects associated with the use of anyeffective pharmaceutical. In the case of bronchodilators, for example,possible side effects commonly include tremor and increased heart rate,and irritation of the hyperreactive airways of many sufferers of airwaydisease.

It is known that optimal deposition of powder particles in the lungoccurs when the particle diameter is under 10 microns, since particleshaving a diameter above this range are preferentially deposited in themouth and throat. However, such fine powder will typically tend eitherto cling to the sides of its container, or to clump, so that a highproportion of the powder takes the form of large, loosely structuredagglomerates of a size much larger than 10 microns, and only a smallpercentage of the powder particles remain within the primary particlediameter range. Certain new types of dry powder inhalers, includingthose described in European Patent Nos. 0 237 507 and 69 715 (e.g., theTURBUHALER®), are able to facilitate the delivery of a pharmaceuticalpowder in which a high proportion of the dispensed particles are ofdiameter in the desired range. This is accomplished by means of amechanism or structural feature which causes the particle agglomeratesto disintegrate during inhalation, yielding a significantly higherproportion of the powder in particles of the primary particle diameterrange below 10 microns. It has generally been thought (see, for example,Bogaard et al. in "Pharmatherapeutica", Vol.5, No.6, 1989) that theefficiency of this new type of inhaler in delivering a clinicallyeffective dose to the patient is comparable to the efficiency ofprevious dry powder inhalers (and therefore also to an MDI). Dosagelevels recommended for a given pharmaceutical in the new type of inhalerhave therefore been of the same order as those recommended for the samepharmaceutical in an MDI.

SUMMARY OF THE INVENTION

It has been found that administration of a pharmaceutically activecompound by means of a dry powder inhaler device which delivers a largeproportion of the powder in the form of particles having a diameter ofless than 10 microns results in a markedly enhanced efficiency ofdelivery to the lungs, compared to delivery from standard pressurizedmetered dose inhalers (MDI's). This enhanced efficiency results from adecrease in the amount of the drug which is wasted due to adhesion tothe interior of the device or to deposition in non-target areas, such asthe mouth and throat of the patient, and is accompanied by a decrease inside effects attributable to such inappropriately deposited drug. Thus,the size of the nominal dose (also termed the metered dose) and the sizeof the dispensed dose used in the method of the invention can besubstantially decreased vis a vis the minimal corresponding doserequired to achieve the same clinical effect as when an MDI is used bythe same patient. By "nominal dose" or "metered dose" is meant the dosewhich is prepackaged in a single-dose inhaler, or which in a multidoseinhaler is automatically measured out of a reservoir in preparation forinhalation. It thus represents the amount of compound measured beforelosses attributable to retention in the device, deposition in the mouthor throat, exhalation, etc. In contrast, "dispensed dose", as usedherein, refers to the amount of compound which actually exits theinhaler. Devices useful in the method of the invention include thebreath-actuated, dry powder inhalers described in EP 0 237 507, EP 69715, WO 92/04069 and WO 93/17728, including the TURBUHALER® multidoseinhaler and the MONOHALER® single-dose inhaler.

The invention thus includes a system for dispensing a clinicallyeffective dose of a pharmaceutically active compound, which systemincludes a dry powder inhaler device containing a powder which includesthe pharmaceutically active compound, wherein

(a) of the metered dose of the compound in the inhaler (the "metered DPIdose"), at least 40% exits the inhaler in the form of powder particlesless than about 10 microns in diameter;

(b) the metered DPI dose is sufficient to produce a clinically effectiveresult in a patient; and

(c) the amount of the compound in the metered DPI dose is not more than70% (preferably not more than 50%) of the minimal amount of the compoundwhich, when dispensed in a pressurized metered dose inhaler, produces anequivalent clinically effective result in the same patient (the "meteredMDI dose"). Preferably, the amount of the compound which exits theinhaler of the invention upon dispensing of the metered DPI dose (the"dispensed DPI dose") is not more than 80% (preferably not more than60%) of the amount of the same compound which exits the MDI upondispensing of the metered MDI dose (the "dispensed MDI dose").

In order to dispense the pharmaceutically active compound in the form ofparticles of the necessary diameter, the powder contained in the inhaleris preferentially made up of primary particles or agglomerates ofprimary particles, which primary particles preferably are micronizedparticles at least 80% (and more preferably at least 90%) of which havea particle diameter of less than about 10 microns. More preferably, atleast 50% (and even more preferably at least 60%) of the primaryparticles have a diameter of less than about 5 microns.

By processing the primary particles into sturdy agglomerates containingmultiple primary particles each, the physical properties of the powderduring storage, handling, and measuring are improved, and less powder islost on the sidewalls of the device. The agglomerates remain friable,however, so that just prior to entering the respiratory track of thepatient, they are readily pulverized into much smaller agglomeratesand/or discrete primary particles of a diameter appropriate fordeposition in the lung (i.e., less than 10 microns, and preferably lessthan 5 microns). In some types of DPI's (e.g., TURBUHLAER andMONOHALER), this deagglomeration is accomplished by a design whichcreates air turbulence within the device from the air flow generated byinhalation through the device.

The pharmaceutically active compound of the present invention may, ifdesired, be contained in a pharmaceutical formulation containingcommonly used additives such as diluents and/or carrier substances whichare generally nontoxic, and chemically inert to the pharmaceuticallyactive compound. For example a carbohydrate such as lactose, glucose,fructose, galactose, trehalose, sucrose, maltose, zylitol, myoinositol,dextrane, starch, or the like (or a hydrate thereof), and especiallylactose, mannitol or myoinositol; or an amino acid such as alanine,betaine, glycine, leucine, or the like, or any additive which willimpart a desired property such as taste or a physiochemical orpharmaceutical property, may be employed. However, it is noted that thepharmaceutically active compound for use in the present inventionrequires no additives and may advantageously be used in its pure form.The powder, with or without additives, may be packaged in a capsule orloaded on an elongate carrying mechanism such as a tape, web or belt,wherein it is used in conjunction with an appropriate inhaler whichdispenses the desired powder particles.

Any inhalable pharmaceutically active compound which can be formulatedinto a powder with the appropriate physiochemical, pharmaceutical andpowder characteristics, as those characteristics are recognized in theart, is suitable for use in the present invention. Such characteristicsinclude, for example, suitable particle size, agglomerability,deagglomerability, flowability, melting point, crystallinity andhygroscopicity. Examples of such pharmaceutically active compoundsinclude drugs for the treatment of diseases of the airways, includingβ2-adrenoreceptor agonists such as salbutamol, terbutaline, rimiterol,fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline,orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol,procaterol, broxaterol, picumeterol, TA-2005, mabuterol and the like,and their pharmacologically acceptable esters and salts; anticholinergicbronchodilators such as ipratropium bromide and the like;glucocorsticosteroids such as betamethasone, fluticasone, budesonide,tipredane, dexamethasone, betamethasone, fluocinolone, triamcinolone,mometasone, D-5519 and the like, and their pharmacologically acceptableesters and salts; anti-allergic drugs such as sodium cromoglycate andnedocromil sodium; expectorants; mucolytics; antihistamines;cyclooxygenase inhibitors; leukotriene synthesis inhibitors; leukotrieneantagonists, PLA2 inhibitors, PAF antagonists, and prophylactics ofasthma. Alternatively, the pharmaceutically active compound could be anyone of several types of inhalable, systemically active drugs, includingantiarrhythmic drugs, tranquilizers, cardiac glycosides, hormones,antihypertensive drugs, antihypotensive drugs, antidiabetic drugs,antiparasitic drugs, anticancer drugs, sedatives and analgesic drugs,antibiotics, antirheumatic drugs, immunotherapeutics, antifungal drugs,vaccines, antiviral drugs, proteins, peptides, vitamins, cell surfacereceptor blockers, and others.

The present invention is especially useful when the pharmaceuticallyactive compound is a β-2 agonist such as terbutaline, salbutamol,formoterol, budesonide or their salts or hydrates, or a mixture of anyof such β-2 agonists (or their salts or hydrates) with a carbohydrate,especially lactose, mannitol or myoinositol. Examples include thefollowing mixtures: ipratropium bromide plus lactose, formoterol plusbudesonide, ipratropium bromide plus budesonide, terbutaline plus sodiumcromoglycate, and terbutaline plus budesonide.

The metered DPI dose of a drug (delivered in accordance with theinvention) can be directly compared to the metered MDI dose of the samedrug, by reference to the published metered MDI dose of that drug (see,e.g., the Physicians' Desk Reference, published by Medical EconomicsData, Montvale, N.J.). Generally the published metered MDI dose can beassumed to be the minimal metered MDI dose that is clinically effective.Alternatively, one of ordinary skill can prepare the drug in both MDIform and in accordance with the system of the invention, and determine,for comparative purposes, the minimal clinically effective metered doseand dispensed dose corresponding to each method. Yet another methodwould permit comparison of (1) the published metered MDI dose of onedrug which targets a given medical condition, with (2) the metered DPIdose (delivered in accordance with the invention) of a second drug whichtargets the same medical condition. Since drugs targeted at the samedisease are commonly not equipotent, even if they act by generally thesame mechanism, the metered dose, dispensed dose, and of course theclinically effective amount of active compound will be different forthese different drugs. For example, the β-2 agonist salbutamol isgenerally accepted as being more potent than the β-2 agonist terbutalinesulphate, 0.1 mg of salbutamol generally being regarded as equipotent to0.25 mg of terbutaline sulphate. Therefore, in any assessment ofefficiency comparing different drugs, equipotent doses ofpharmaceutically active compounds should be directly compared. Asdisclosed herein, these recommended doses can be reduced when the systemof the invention, rather than an MDI, is used to dispense the drugs. Forexample, the metered dose of each of salbutamol, budesonide andterbutaline may be reduced by a factor of two, compared to the metereddose dispensed from an MDI for an equivalent clinically therapeuticeffect, in accordance with the present invention.

Also within the invention is a method for dispensing a clinicallyeffective dose of a pharmaceutically active compound, which methodincludes the steps of identifying a patient in need of the compound(i.e., a patient suffering from a medical condition treatable with thecompound), and causing the patient to inhale the compound from the drypowder inhaler system of the invention, as described above. Preferably,the patient is an adult, and the metered DPI dosage is no more than 70%of the metered MDI dosage appropriate for an adult of the same bodyweight. Alternatively, the patient is a child, and the metered DPIdosage is no more than 70% of the metered MDI dosage appropriate for achild of the same body weight. This method is thus useful for thetreatment of a medical condition which is treatable with thepharmaceutically active compound in inhalable form.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph comparing the particle size distribution ofparticles exiting a TURBUHALER inhaler and a MDI.

FIG. 2 is a graph comparing the clinical effect of various cumulativemetered doses of salbutamol inhaled from a dry powder inhaler system ofthe invention, with the clinical effect of the same cumulative metereddoses inhaled from a MDI. Clinical effect is expressed as mean values offorced expiratory volume in one second, FEV₁ (L), before dosing.

FIG. 3 is a graph comparing the mean values of FEV₁ (L) in percent ofmean baseline, representing clinical effect, in patients given variouscumulative metered doses of salbutamol via a MDI or a dry powder inhalersystem of the invention.

FIG. 4 is a bar graph comparing lung deposition of salbutamol inhaledvia a pressurized MDI at the flow rate of 30-60 L/min, or via a drypowder inhaler system of the invention, at a mean peak inspiratory flowof 64 L/min, by healthy volunteers.

DETAILED DESCRIPTION

The invention will now be illustrated by Examples which are intended toillustrate but not limit the scope of the invention.

EXAMPLE 1 Particle size distribution

In vitro studies have shown that the delivery of powdered budesonide bythe TURBUHALER inhaler at inspiratory flows of 60 liters/minute leads toa greater proportion of fine particles than does delivery by an MDI(PULMICORT™ budesonide MDI, AB Astra, Sweden). The measurements wereperformed with a four-stage (>13, 7-13, 4-7, and 1-4 microns) cascadeimpactor, which operates at a flow rate of 60 liters/minute. Five unitsof each device were separately tested. The results, presented in FIG. 1,illustrate that, under the conditions tested, more than half of theparticles delivered by the TURBUHALER device made it to the stagecorresponding to a diameter of 1 to 4 microns, and about two-thirdsregistered 7 microns or less.

EXAMPLE 2 TURBUHALER v. MDI (Budesonide)

In order to determine the absolute systemic availability and the amountof budesonide deposited and absorbed in the lung after inhalation viaTURBUHALER and via an MDI, 24 healthy subjects were given budesonide 1mg as five inhalations of 200 micrograms each, via TURBUHALER inhaler orvia MDI, and 0.5 mg intravenously, on separate study days. Budesonidelevels were determined in plasma by a LC-MS method. The amount ofbudesonide absorbed in the lung was calculated on the assumption of anavailability of swallowed budesonide of 13%. Furthermore, absorption inthe lung was calculated in 13 of the subjects after inhalation withconcomitant oral dosing of charcoal to prevent absorption of budesonidefrom the gastrointestinal track. There was good conformity between thetwo modes of calculation.

From TURBUHALER, the geometric mean of the absolute systemicavailability of budesonide was 38%. For the MDI, this figure was 28%.CMAX and TMAX were 3.6 nmol/l and 0.3 hours with TURBUHALER, and 2.3nmol/l and 0.5 hours with the MDI. The geometric mean of the amount ofbudesonide deposited and absorbed in the lung was 32% (16%-59%) forTURBUHALER and 15% (3%-47%) for the MDI. This shows a lung deposition ofbudesonide from TURBUHALER which is twice that from an MDI, and lessvariable, demonstrating that a lower metered dosage may be used whenTURBUHALER is employed.

EXAMPLE 3 TURBUHALER v. MDI (Terbutaline)

Eight healthy volunteers were administered terbutaline sulphate taggedwith (99 m)Tc, using a TURBUHALER inhaler or a MDI on two separate daysat least 48 hours apart in randomized cross-over fashion. In order todeposit approximately 10 MBq (99 m)Tc in the body on each study day,four doses of terbutaline sulphate (total 1 mg) were given by MDI andtwo doses of terbutaline sulphate (total 1 mg) were given by TURBUHALER.Administration of radioactive aerosol was performed with the inhalerconnected in series with a Vitalograph MDI-compact spirometer(Vitalograph Ltd., UK) modified for measuring inhalation flows. Thetarget average inhalation flow rate for the MDI trials was 30 l/min, andthe target peak inhalation flow rate for the TURBUHALER inhaler trialswas 60 l/min. These flow rates are believed to optimize drug delivery tothe lungs for the two respective devices. After inhalation, thevolunteers were instructed to hold their breath for 10 seconds beforeexhaling through an exhalation filter (Pall Ultipor, UK) that retainsterbutaline inhaled into, but not deposited in, the lungs. The MDI wasactuated by an investigator during the course of inhalation. Lungfunction tests were performed before and after inhalation of thelabelled terbutaline to ensure that no deterioration in lung functionhad occurred. Immediately after inhalation of a study drug, posteriorand anterior views of the lungs and a lateral view of the oropharynxwere taken by gamma camera (General Electric Maxicamera) connected online to a Nodecrest computer system. Gamma radiation from the mouthpieceand exhalation filter was also measured. All images were stored onmagnetic tape for subsequent data analysis. From these measurements thefraction of the metered dose into the lungs could be determined. Themeasurements, when adjusted to take account of an observed mismatchbetween the distributions of unlabelled drug, labelled drug andradiolabel for the TURBUHALER inhaler, gave a mean value of 29.3% fortotal lung deposition (TURBUHALER), compared with 16.7% for a MDI. Thesefigures indicate the feasibility of using a lower metered dose whenTURBUHALER is employed rather than a MDI.

EXAMPLE 4 TURBURALER v. MDI (Salbutamol)

The relative efficacy of cumulative doses (100 micrograms up to 1600micrograms) of salbutamol in TURBUHALER and salbutamol in a MDI(Ventolin, Glaxo) was compared in 12 patients with reversibleobstructive airway disease. The results, shown in FIGS. 2 and 3,indicate that salbutamol delivery is more efficient from the TURBUHALERinhaler than from the commercially marketed MDI. Therefore, the metereddose of salbutamol in a TURBUHALER system can be lower than the MDImetered dose, for the same clinical effect.

EXAMPLE 5 Particle Distribution (salbutamol)

The absolute pulmonary deposition of salbutamol inhaled via TURBUHALERand a MDI was investigated. Salbutamol was mixed with lactose in orderto achieve lower dosing without affecting the dosing accuracy.Individual data from 7 healthy volunteers indicated a difference indeposition favoring TURBUHALER. The results are presented in FIG. 4.

EXAMPLE 6 MONOHALER (Budesonide)

Particle size distribution from the MONOHALER single dose inhaler hasbeen found to be comparable with that of the TURBUHALER multidoseinhaler (data not shown). This indicates that this single-dose inhaleralso is appropriate for use in the system and methods of the invention,and an efficiency of delivery comparable to that of the TURBUHALER canbe expected.

Other embodiments are within the following claims.

What is claimed is:
 1. A method for dispensing a dose of apharmaceutically active compound selected from the group consisting offormoterol and a salt, hydrate or ester of formoterol, which methodcomprises(1) identifying a patient in need of treatment with saidcompound; (2) providing a breath-actuated, dry powder inhaler devicecontaining a powder comprising said compound, wherein(a) said powderstored within said device consists essentially of agglomerates ofprimary particles, at least 80% of said primary particles having adiameter of less than about 10 microns, (b) said device comprises ametered dose of said compound sufficient to produce a predeterminedclinically effective result in said patient, said metered dosecontaining an amount of said compound less than or equal to 70% byweight of the amount of said compound which would be required to producesaid predetermined equivalent clinically effective result were thecompound administered by a standard pressurized metered dose inhaler;and (c) said device comprises a means for using air turbulence to obtainsubstantial deagglomeration of the primary particles prior to theirexiting said device, so that of said metered dose, at least 40% exitssaid device in the form of unagglomerated particles less than about 10microns in diameter, and (3) administering said metered dose to thepatient by causing the patient to inhale through said device, therebycreating sufficient air turbulence in said device to cause said metereddose of agglomerated primary particles to be substantiallydeagglomerated prior to exiting said device, such that at least 40% ofsaid metered dose exits said device in the form of unagglomeratedparticles less than about 10 microns in diameter.
 2. The method of claim1, wherein said inhaler device is a multidose, breath-activated inhaler.3. The method of claim 1, wherein said powder additionally comprises acarbohydrate.
 4. The method of claim 1, wherein said powder additionallycomprises an amino acid.